title: Immunologic reconstitution during PEG-ADA therapy in an unusual mosaic ADA deficient patient.
abstract: We report detailed genetic and immunologic studies in a patient diagnosed with adenosine deaminase (ADA) deficiency and combined immune deficiency at age 5 years. At the time of diagnosis, although all other lymphocyte subsets were depleted, circulating CD8(+) T cells with a terminally differentiated phenotype were abundant and expressed normal ADA activity due to a reversion mutation in a CD8(+) T cell or precursor. Over the first 9 months of replacement therapy with PEG-ADA, the patient steadily accumulated mature naïve CD4(+) and CD8(+) T cells, as well as CD4(+)/FOXP3(+) regulatory T cells, consistent with restoration of a functional cellular immune system. While CD19(+) naïve B cells also accumulated in response to PEG-ADA therapy, a high proportion of these B cells exhibited an immature surface marker phenotype even after 9 months, and immunization with neoantigen bacteriophage varphiX174 demonstrated a markedly subnormal humoral immune response. Our observations in this single patient have important implications for gene therapy of human ADA deficiency, as they indicate that ADA expression within even a large circulating lymphocyte population may not be sufficient to support adequate immune reconstitution. They also suggest that an immature surface marker phenotype of the peripheral B cell compartment may be a useful surrogate marker for incomplete humoral immune reconstitution during enzyme replacement, and possibly other forms of hematopoietic cell therapies.
authors.affiliation: Department of Pediatrics, University of Washington and Seattle Children's Hospital Research Institute, Seattle, WA, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Ines
authors.initials: I
authors.lastname: Santisteban
authors.forename: Lauri M
authors.initials: LM
authors.lastname: Burroughs
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hershfield
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scharenberg
mesh_terms: D000243:Adenosine Deaminase / Q000097:blood / Q000172:deficiency* / Q000276:immunology / Q000627:therapeutic use; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D010584:Bacteriophage phi X 174 / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D002675:Child, Preschool; D006801:Humans; D008297:Male; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
chemical_list: D000243:Adenosine Deaminase; C051409:pegademase bovine